Dysfunction throughout the arterial vasculature is responsible for significant morbidity/mortality in patients with type 2 diabetes (DM 2) and metabolic syndrome (MS). The arterial vasculature in healthy subjects responds to insulin and this response is impaired with insulin resistance (IR). Available noninvasive methods allow comprehensive evaluation of insulin action at each of 3 levels of arterial vasculature, including conduit, resistance, and microvascular vessels. Here we propose to use measures of pan-arterial vascular function and insulin sensitivity to address several fundamental questions related to the impact of insulin resistance on vascular function. Our general hypothesis is that IR, either induced experimentally or as occurs with MS and DM 2, impairs vascular function at all levels of the arterial vasculature. We further hypothesize that treatments previously shown to improve vascular outcomes will effectively improve this pan-arterial dysfunction. If these hypotheses prove correct, they may provide: A) a functional mechanism to explain the linkage between IR and cardiovascular diseases (CVD);B) a rationale for the previously observed salutory clinical effects of metformin, type 1 angiotensin II receptor (AT1R) blockers, mineralocorticoid receptor (MR) blockers and diet/exercise on CVD and;C) a basis to suggest that early assessment of pan-arterial function affords a platform to improve candidate treatment selection for later clinical trials. In Aim 1, we will measure pan-arterial vascular function and insulin responsiveness in healthy subjects and assess the effect of a single high-fat meal on insulin's vascular and metabolic actions. In Aim 2, in subjects with MS, we will again measure pan-arterial vascular function and insulin sensitivity before and following 12 weeks treatment with a placebo or metformin with or without a diet low in saturated fat combined with exercise training in a randomized 2 X 2 design. In Aim 3, in metformin-treated DM 2 subjects, we will characterize pan-arterial vascular function and vascular insulin sensitivity before and following 12 weeks treatment with an AT1R blocker, a MR blocker or a placebo in a blinded, crossover study. PUBLIC HEALTH RELEVANCE: As CVD remains the major cause of morbidity/mortality in DM2 and MS in the post-statin and post- antihypertensives era and as arterial dysfunction independently predicts CVD, elucidation of the linkage between IR, arterial dysfunction, and CVD is vital. By examining insulin's action on 3 levels of the arterial vasculature in healthy individuals and patients with MS or DMS 2, we can improve both our understanding of the mechanisms of vascular IR and our ability to efficiently test potential new therapies.